Cited by 235Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersWilliams Syndrome Research

The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders

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Levitt, Pat, Campbell, Daniel B.·2009·Journal of Clinical Investigation

Abstract

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.

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  • Molecular and pathological evidence implicates later pregnancy and early postnatal life, pointing to altered neuronal connectivity and signaling pathways under intense development in these periods.

    “Later pregnancy and early postnatal life are additionally implicated by accumulating molecular and pathological evidence pointing to altered neuronal connectivity and a resultant perturbation in signaling pathways, systems under intense development in these periods.25,26”
  • Evidence supporting environmental contributions to ASD risk includes incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation.

    “Evidence supporting environmental contributions to ASD risk include observations of incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation, whereby a significant percentage of carriers do not express autistic phenotypes [ 14 , 19 , 22 ].”

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Authors
Levitt, P., & Campbell, D. B.
Affiliations
Vanderbilt University (US)
Corresponding author
Levitt, Pat
Venue
Journal of Clinical Investigation
Published
2009-04-01
Volume
119
Issue
4
Pages
747-754
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2018736722
Cited by
234
References
115
Citations by year
2026: 4 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 18 · 2016: 13 · 2015: 14 · 2014: 27 · 2013: 16 · 2012: 26
FWCI
1.91
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
Keywords
autism spectrum disorder, genetic etiology, de novo mutations, common genetic variants, ERK signaling, PI3K signaling, receptor tyrosine kinase, neurodevelopmental syndrome, neurodevelopmental disorders
MeSH terms
Alleles, Autistic Disorder, Child, Female, Humans, Male, Models, Genetic, Models, Neurological, Mutation, Proto-Oncogene Proteins, Genetic Variation, Signal Transduction, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Genetic Predisposition to Disease, MAP Kinase Signaling System, Genome-Wide Association Study

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